Synthesis and biological studies of 2-aminothiophene derivatives as positive allosteric modulators of glucagon-like peptide 1 receptor

• Published in: Bioorganic & medicinal chemistry 2024-09, Vol.111, p.117864, Article 117864
• Main Authors: Campbell, Jeffrey A., Do, Phu, Li, Zhiyu, Malik, Faisal, Mead, Christopher, Miller, Nick, Pisiechko, Christopher, Powers, Kimberly, Li, Zhijun
• Format: Article
• Language: English
• Subjects: 2-Aminothiophene; Allosteric Regulation - drug effects; Animals; Blood Glucose - drug effects; Blood Glucose - metabolism; Dose-Response Relationship, Drug; Glucagon-like peptide 1 receptor; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - metabolism; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Insulin - metabolism; Insulin secretion; Mice; Molecular Structure; Obesity and type-2 diabetes; Positive allosteric modulators; Sitagliptin Phosphate - chemical synthesis; Sitagliptin Phosphate - chemistry; Sitagliptin Phosphate - pharmacology; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2024.117864

[Display omitted] •A series of 2-aminothiophene derivatives was designed and synthesized.•These derivatives were evaluated for their positive allosteric modulating effect on GLP1R.•Compound 7 significantly lowered blood plasma glucose level through In vivo studies using CD1 mice at a dose of 10 mg/kg.•Compound 7 is a promising lead compound for treating obesity and type 2 diabetes. As a step toward the development of novel small-molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes, obesity, and heart diseases, we discovered a novel 2-amino-thiophene (2-AT) based lead compound bearing an ethyl 3-carboxylate appendage. In this work, we report the syntheses and biological studies of more than forty 2-AT analogs, that have revealed a 2-aminothiophene-3-arylketone analogue 7 (MW 299) showing approximately a 2-fold increase in insulin secretion at 5 μM when combined with the GLP-1 peptide at 10 nM. In vivo studies using CD1 mice at a dose of 10 mg/kg, clearly demonstrated that the blood plasma glucose level was lowered by 50% after 60 min. Co-treatment of 7 with sitagliptin, an inhibitor of GLP-1 degrading enzyme Dipeptidyl Peptidase IV, further confirmed 7 to be an effective PAM of GLP-1R. The small molecular weight and demonstrated allosteric modulating properties of these compound series, show the potential of these scaffolds for future drug development.